Info

uncharacterizedf

glimepiride

aAvandia product information (20-0ct-2008 labeling).

^Calculated (Accelrys Software, ACD Labs), as reported via SciFinder (Chemical Abstracts Service) accessed Spring 2009. The proximity of the two pKa values renders experimental determination difficult, as noted by Giaginis et al.c NMR spectroscopic determination, with deconvolution, would be necessary, but such determinations were not discovered in the literature.

cGiaginis, C., Theocharis, S., and Tsantili-Kakoulidou, A.: J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 857(2):181-187, 2007.

dCox, P. J., Ryan, D. A., Hollis, F. J., et al.: Drug. Metab. Dispos. 28(7):772-780, 2000. eBaldwin, S. J., Clarke, S. E., and Chenery, R. J.: Br. J. Clin. Pharmacol. 48(3):424-432, 1999. fActos product information (11-Dec-2008 labeling).

gJaakkola, T., Backman, J. T., Neuvonen, M., et al.: Br. J. Clin. Pharmacol. 61(1):70-78, 2006, and references therein.

hsa, human serum albumin.

aAvandia product information (20-0ct-2008 labeling).

^Calculated (Accelrys Software, ACD Labs), as reported via SciFinder (Chemical Abstracts Service) accessed Spring 2009. The proximity of the two pKa values renders experimental determination difficult, as noted by Giaginis et al.c NMR spectroscopic determination, with deconvolution, would be necessary, but such determinations were not discovered in the literature.

cGiaginis, C., Theocharis, S., and Tsantili-Kakoulidou, A.: J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 857(2):181-187, 2007.

dCox, P. J., Ryan, D. A., Hollis, F. J., et al.: Drug. Metab. Dispos. 28(7):772-780, 2000. eBaldwin, S. J., Clarke, S. E., and Chenery, R. J.: Br. J. Clin. Pharmacol. 48(3):424-432, 1999. fActos product information (11-Dec-2008 labeling).

gJaakkola, T., Backman, J. T., Neuvonen, M., et al.: Br. J. Clin. Pharmacol. 61(1):70-78, 2006, and references therein.

hsa, human serum albumin.

playing the major role in both transformations, and some involvement of CYP2C9.21,47 The sulfate conjugate M10 is the predominant circulating metabolite by 4-hour postdose. The extraordinarily high plasma protein binding of this metabolite (and the N-demethylated sulfate conjugate M4) in humans accounts for the lengthy residence time of the radioactivity in the body, despite the relatively short pharmacokinetic half-life (4-4.5 hours) of rosiglitazone itself.

Pioglitazone is 5-(4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl)thiazolidine-2,4-dione, and is available in tablets containing the hydrochloride salt alone (Actos in the United

Figure 20.19 • Important biotransformations of rosiglitazone. (PAP, 3'-phospho-adenosine-5'-phosphate; PAPS, 3'-phosphoadenosine-5'-phosphosulfate.)
Figure 20.20 • Important biotransformations of pioglitazone. (GSH, glutathione.)

States, Glustin in Europe and Zactos in Mexico), or in combination with glimepiride (Duetact, see "Glimepiride" previously in this chapter) or metformin (Actoplus Met; see under "Metformin" later in this chapter).

Pioglitazone is extensively biotransformed,48-50 and at least three metabolites are known to be pharmacologically active, although only two of these (M-IV and M-III, see Fig. 20.20) are thought to significantly contribute to the therapeutic effects.51 CYP2C8 and CYP3A4 predominantly account for the observed biotransformations, with the former playing a greater role. Ring-opened metabolites (M-X, M-A) have also been identified in human liver mi crosomes,48 but although the pathway leading to these may play a role in the hepatotoxicity of troglitazone, pioglita-zone seems not to have the same liability to any significant extent, most likely because the pioglitazone doses are sufficiently lower (by about 10-fold) than those that had been needed with troglitazone.

Biguanides

The biguanide class of insulin-sensitizing agents includes only one marketed medicinal in the United States, namely metformin (Fig. 20.21), but this drug is a first-line drug in the

metformin phenformin buformin

Figure 20.21 • Structures of biguanide hypoglycemic agents.

treatment of type 2 diabetes, for which it is prescribed heavily, alone and in combinations. Having been brought to market in France in 1979 (though not until 1995 in the United States), metformin has a long history of use, despite which fact the mechanisms underlying its effects remain uncer-tain.52-56 Activation by metformin of adenosine monophos-phate-activated protein kinase (AMPK) has commonly been stated as the molecular mechanism in recent years; however, the as-yet-to-be-identified primary target(s) must either be upstream of AMPK, or trigger downstream mechanisms that deliver stimulatory feedback upstream of AMPK, or cause changes in crosstalk mechanisms (such as those involving insulin receptor substrate 1) to indirectly enhance AMPK action, or some combination thereof. A month of chronic metformin therapy increases basal levels of protein kinase C type zeta (PKQ) in the muscle tissue of type 2 diabetics, in turn restoring glucose handling to a more normal state,57,58 and PKC^ acts through serine-threonine kinase 11 (STK11/LKB1) to modulate AMPK activity;55 however, PKQ is clearly not the direct macromolecular target of metformin, either. Some evidence suggests that subtle metformin-caused changes in mitochondrial membrane potential may circuitously bring about the beneficial collateral changes in other pathways, including the aforementioned PKC^STK11^AMPK signaling chain; metformin inhibits complex I (NADH:ubiquinone dehydrogenase) of the electron transport chain.59,60 In any case, over a period of weeks, metformin enhances the sensitivity of various cells of the body to insulin. Recently, much activity has centered on fully characterizing the roles of the organic cation transporter 1 (OCT1), the functioning of which is clearly essential to metformin's action.61 Presumably, this transporter allows the drug to reach its intracellular target(s), and pharmacogenomic variations with respect to the OCT1 complex that decrease or abolish the effectiveness of metformin have been identi-fied.61,62 OCT1 is richly expressed in those hepatocytes participating most directly in the regulation of glucose levels.

The bioavailability of metformin at normal clinical doses ranges from 40% to 60%, which is quite high for such an extensively ionized and hydrophilic drug (calculated log D--6 at pH 7)63; the biguanide moiety is extremely basic (Fig. 20.22), thus, metformin exists almost

Figure 20.22 • Biguanides: basis of the "biguanide" designation, tautomeric forms of the protonated species, and canonical (resonance) structures representing derealization of the positive charge in the conjugate acid.

exclusively as protonated, positively charged molecular species throughout the entire physiological pH range. Absorption from the gut was recently shown to occur by a paracellular route, which, surprisingly, was found to be saturable;64 the exact molecular basis for this observation, if yet known, has not been reported. Renal elimination is also transporter mediated (active tubular secretion). Elimination of absorbed metformin is essentially 100% by the kidneys, at a rate about 3.5-fold creatinine clearance, thus renal insufficiency precludes metformin pharmacotherapy because of the resultant risk of lactic acidosis that otherwise essentially never occurs with this drug. Other drugs of this class (phenformin, buformin, structures Fig. 20.21) were abandoned because of lactic acidosis-linked fatalities, even though the incidence with phenformin was actually quite rare. Little metformin binding to plasma proteins occurs, but partitioning into erythrocytes is considerable, significantly impacting the PK of this drug.

Metformin is n,n-dimethylimidodicarbonimidic di-amide, but can accurately and much more simply be named as 1,1-dimethylbiguanide. Metformin is available, as its hy-drochloride salt, in tablets ranging in strengths from 500-mg to 1-g (Glucophage, numerous generics), extended-release tablets (Fortamet, Glumetza), and an oral solution (Riomet); and in combinations with rosiglitazone (Avandamet), pioglitazone (Actoplus Met), glipizide (Metaglip, generics), glyburide (Glucovance), repaglinide (Prandimet), and most recently, sitagliptin (Janumet).

a-Glucosidase Inhibitors

Medicinals acting as a-glucosidase inhibitors slow the breakdown of disaccharides (notably sucrose) and starch-

derived polysaccharides into monosaccharides in the gastrointestinal (GI) tract, delaying production and thereby absorption of glucose following consumption of meals. This approach to reducing peak postprandial serum glucose levels is highly effective, with the caveat that these drugs cause very uncomfortable GI side effects in a high percentage of patients; fortunately, artful inception of therapy, with monitoring, can greatly reduce the impact of this liability. The a-glucosidase inhibitors marketed in the United States include acarbose and miglitol; an additional a-glucosidase inhibitor, voglibose, is marketed in Japan and several other countries including Brazil (structures Fig. 20.23).

Digestion of amylose and amylopectin forms of starch begins with reactions catalyzed by a pair of related a-amy-lases, which are endoglucosidase enzymes contained in pancreatic secretions. Complete digestion also requires de-branching for amylopectin, and further cleavage of various disaccharides and small oligosaccharides. These reactions are catalyzed by a-glucosidases, which are a highly similar set of enzymes that cleave the glycoside linkage between particular sugar moieties; more specifically, hydrolysis occurs at the acetal oxygen bridging the C1 of a glucose residue and either C4 or C6 of another glucose in a-(1^4) or a-(1^6) linkage (maltose or isomaltose, respectively; see Fig. 20.24), but not j8-(1^4) glucose-glucose linkages (as in cellobiose) or the j8-(1^4) galactose-glucose linkage in lactose. a-Glucosidases are exoglycosidases, cleaving terminal glucose residues from the nonreducing end of an oligosaccharide. Four separate maltase enzymes found in the luminal membrane of enterocytes (more specifically, the brush-border epithelial cells) actually constitute these activities: two associated with "sucrase-isomaltase" (SI)

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